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Eur J Echocardiography 7 Suppl. 2 (2006) S22–S29<br />

<strong>Tissue</strong> <strong>viability</strong> <strong>by</strong> <strong>contrast</strong> <strong>echocardiography</strong><br />

Luciano Agati a, *, Stefania Funaro b , Mariapina Madonna a ,<br />

Mariella Montano a , Emanuela Berardi a , Maria Novella Picardi a ,<br />

Carmine Dario Vizza a , Alessandra Labbadia a , Marco Francone c ,<br />

Iacopo Carbone c , Francesco Fedele a<br />

a Department of Cardiology, La Sapienza University of Rome; b Department of Cardiology, Catholic<br />

University of Campobasso; c Department of Radiology, La Sapienza University of Rome, Italy<br />

KEYWORDS<br />

Contrast media;<br />

Microcirculation;<br />

Myocardial infarction;<br />

<strong>Tissue</strong> <strong>viability</strong>.<br />

Introduction<br />

Despite improved clinical care, myocardial infarction<br />

and sudden death still remain the leading<br />

Abstract Residual tissue <strong>viability</strong> within the infarct area is one of the major<br />

determinants of regional functional recovery after acute myocardial infarction,<br />

playing also a protective role against LV remodelling. However, <strong>viability</strong> and<br />

functional recovery are not synonymous: functional recovery is only one of the<br />

aspects of <strong>viability</strong>. Several studies have shown how important it is to maintain<br />

perfusion independently from functional recovery. In patients with an extensive<br />

endocardial necrosis and a preserved normal perfusion in the middle and epicardial<br />

myocardium layers, even though functional recovery does not occur, remodelling<br />

processes may be attenuated. <strong>Tissue</strong> <strong>viability</strong> may be detected using several<br />

different methods. Perfusion-based techniques (i.e. PET, SPECT, MRI and MCE) are<br />

more accurate in predicting global function and LV remodelling whereas inotropic<br />

reserve-based methods (i.e. DE) are more accurate in predicting functional recovery.<br />

Several studies support the hypothesis that either LV remodelling or the possibility<br />

of myocardial dysfunction to recover are strictly dependent on the extent of<br />

microvascular damage. To date, myocardial <strong>contrast</strong> <strong>echocardiography</strong> and magnetic<br />

resonance imaging have shown to be very effective techniques for assessing<br />

microvascular perfusion. Our initial experience showed a very close correlation<br />

between these two perfusional techniques. In particular <strong>by</strong> MCE, it has been<br />

demonstrated that the persistence of residual anterograde or retrograde blood flow<br />

within the infarct zone can maintain myocardial <strong>viability</strong> for a prolonged time span.<br />

The incidence of LV remodelling is significantly lower in dysfunctioning but still<br />

perfused segments than in non-perfused ones. Therefore MCE can be used to identify<br />

viable segments that may help to prevent infarct expansion and remodelling, and<br />

thus improve patient outcomes.<br />

© 2006 The European Society of Cardiology. Published <strong>by</strong> Elsevier Ltd. All rights<br />

reserved.<br />

* Corresponding author. Luciano Agati, MD. Associate Professor<br />

of Cardiology, Department of Cardiology, “La Sapienza”<br />

University of Rome, Italy. E-mail address: luciano.agati@uniroma1.it<br />

(L. Agati).<br />

causes of death in western countries. Recent data<br />

from the CRUSADE trial 1 aimed to assess the<br />

impact of congestive heart failure (CHF) after<br />

non ST-segment elevation myocardial infarction<br />

(NSTEMI) showed that CHF frequently occurs<br />

in these patients and is associated with less<br />

aggressive treatment and higher risk of mortality.<br />

1525-2167/$30 © 2006 The European Society of Cardiology. Published <strong>by</strong> Elsevier Ltd. All rights reserved.<br />

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<strong>Tissue</strong> <strong>viability</strong> <strong>by</strong> <strong>contrast</strong> <strong>echocardiography</strong> S23<br />

Thus, there is a strong need for preventing postischemic<br />

left ventricular (LV) dysfunction and for<br />

new markers able to identify high risk patients<br />

after acute coronary syndromes.<br />

Prevention of post-ischemic LV dysfunction<br />

The best way to prevent LV dysfunction after acute<br />

myocardial infarction (AMI) is to reduce the time<br />

to treat. There is a general agreement based on<br />

several multicentre trials that independently of<br />

reperfusion strategies, time to reperfusion is the<br />

key determinant of myocardial salvage in patients<br />

with AMI 2 . However, whereas primary percutaneous<br />

coronary intervention (PPCI) or fibrinolysis<br />

are equally recommended for patients presenting<br />

within 3 h of symptom onset, PPCI is superior to<br />

lysis when reperfusion starts 3 h after symptom<br />

onset 3 . A recent survey showed that


S24 L. Agati et al.<br />

Fig. 1. New software is used to identify and track the<br />

endocardial border during contraction. The illustration shows<br />

the endocardial contours at end-diastole and the arrows the<br />

excursion during systole.<br />

an improvement in the definition of all cavities and<br />

borders (Fig. 2).<br />

To increase the diagnostic capability of <strong>echocardiography</strong><br />

we do not need fast but non-diagnostic<br />

procedures in our echo labs. We absolutely need<br />

to spend some more time to produce good and<br />

diagnostic images and this is now feasible with<br />

<strong>contrast</strong>.<br />

Assessment of myocardial infarction and residual<br />

ischemia after AMI<br />

Two recent studies showed in a large series of patients<br />

the additional value of myocardial <strong>contrast</strong><br />

echo in the diagnosis of acute coronary syndrome.<br />

In the first study 21 the authors hypothesized that<br />

regional function and myocardial perfusion may<br />

Fig. 2. Live 3D. Left ventricular opacification for endocardial border enhancement. By using Tomtec software, endocardial surface is<br />

automatically recognized and a 3D reconstruction of LV volume is obtained. Upper panel: two perpendicular long-axis views. Lower<br />

panel: (left) short axis, (right) 3D reconstruction of LV volume.<br />

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<strong>Tissue</strong> <strong>viability</strong> <strong>by</strong> <strong>contrast</strong> <strong>echocardiography</strong> S25<br />

be superior to the TIMI score for diagnosis and<br />

prognosis in patients presenting to the emergency<br />

department with chest pain and a non-diagnostic<br />

electrocardiogram. They were able to show that<br />

myocardial <strong>contrast</strong> echo can rapidly and accurately<br />

provide short-, intermediate- and long-term<br />

prognostic information in patients presenting to<br />

the emergency department with suspected cardiac<br />

chest pain even before serum cardiac markers<br />

are known. The second study 22 showed that in<br />

patients with regional wall motion abnormalities,<br />

the contemporary presence of abnormal perfusion<br />

increases the likelihood of adverse events in the<br />

follow-up.<br />

In the first large study 23 in patients undergoing<br />

dobutamine stress for detecting residual ischemia<br />

after acute myocardial infarction, the additional<br />

role of myocardial perfusion over wall motion in<br />

identifying the amount of myocardium at risk has<br />

been clearly demonstrated. Patients with normal<br />

perfusion have a better outcome than patients with<br />

normal wall motion.<br />

The explanation for the additional prognostic<br />

value of myocardial <strong>contrast</strong> perfusion <strong>echocardiography</strong><br />

is related to the way in which bubbles<br />

behave: during hyperaemia all bubbles arrive<br />

quickly in the ROI and at 2 frames after the flash<br />

there is complete replenishment of the bubbles<br />

into the myocardium; if there is a stenosis,<br />

bubbles arrive more slowly and at 1–2 frames<br />

after flash it is not possible to see a complete<br />

replenishment of ROI but only after 4–8 frames.<br />

The majority of inducible perfusion abnormalities<br />

occur at an intermediate phase of stress, without<br />

wall motion abnormalities, thus explaining the<br />

higher sensitivity of perfusion imaging over wall<br />

motion. Myocardial <strong>contrast</strong> echo may be of great<br />

help in identifying residual area of ischemia into<br />

the infarction area or surrounding area.<br />

Assessment of microvascular perfusion within the<br />

infarct area (true infarct size)<br />

<strong>Tissue</strong> <strong>viability</strong> is the main determinant of functional<br />

recovery after acute myocardial infarction.<br />

However, myocyte <strong>viability</strong> and functional recovery<br />

are not synonymous, but the latter has to be<br />

considered as one aspect of the former 24 . <strong>Tissue</strong><br />

<strong>viability</strong> is also very important to prevent postischemic<br />

LV remodelling. In patients with extensive<br />

subendocardial necrosis but preserved normal<br />

perfusion in mid wall and epicardium, even though<br />

functional recovery is not observed, attenuation of<br />

the LV remodelling process may occur. Thus, all the<br />

efforts to assess and maintain tissue <strong>viability</strong> are<br />

strongly justified.<br />

Several techniques 25–33 have been developed<br />

to identify dysfunctional but viable myocardium.<br />

Perfusion-based techniques (i.e. PET, SPECT, MRI<br />

and MCE) are more accurate in predicting global<br />

function recovery and LV remodelling whereas<br />

inotropic reserve-based methods (i.e. dobutamine<br />

stress echo) are more accurate in predicting<br />

regional functional recovery 25–33 . Dobutamine<br />

stress is the best method to assess regional<br />

functional recovery 28,29 . Several studies 30–33 agree<br />

that dobutamine has a high positive predictive accuracy<br />

for predicting functional recovery whereas<br />

thallium has high negative predictive value in<br />

predicting functional recovery, as have MCE or MRI.<br />

Therefore nuclear imaging is highly sensible for cell<br />

<strong>viability</strong> but it overestimates functional recovery.<br />

Dobutamine <strong>echocardiography</strong> is highly specific but<br />

it underestimates the amount of <strong>viability</strong>; MCE<br />

and MRI are the only techniques able to evaluate<br />

microvascular integrity which is a “conditio sine<br />

qua non” for cell <strong>viability</strong> and later functional<br />

improvement 28–33 .<br />

The role of <strong>contrast</strong> <strong>echocardiography</strong> and<br />

magnetic resonance in predicting wall motion<br />

recovery and LV remodelling in patients with<br />

previous MI has been elucidated <strong>by</strong> several<br />

studies 25–33 . In particular, MRI may be considered<br />

as the reference method to detect scar tissue in<br />

post-ischemic LV dysfunction 25–27 . Late gadolinium<br />

enhancement (LGE) is inversely related to recovery<br />

of systolic thickening. There is a >7-fold increase in<br />

major adverse coronary events in patients with late<br />

enhancement, finally there is a close correlation<br />

between LGE and life-threatening arrhythmias.<br />

Thus, the extent of scar tissue can be considered<br />

as a new marker for identifying patients at high<br />

risk of sudden cardiac death caused <strong>by</strong> ventricular<br />

dysrhytmia and who could be candidates for ICD<br />

implantation.<br />

Similar data has been obtained <strong>by</strong> MCE, as<br />

depicted in Figs. 3 and 4. Balcells et al. 34 showed a<br />

close correlation between <strong>contrast</strong> score at 3 days<br />

after MI and wall motion score at 4 weeks. Lepper<br />

et al. 35 and Badano et al. 36 demonstrated that the<br />

best predictor of left ventricular recovery is the<br />

extent of perfusion defect.<br />

In our study 37,38 we showed a closer correlation<br />

between <strong>contrast</strong> defect at day 1 and wall motion<br />

abnormalities at follow-up than between the initial<br />

and final extent of wall motion abnormalities<br />

(Fig. 5). In other words, the status of microvascular<br />

perfusion after reperfusion is the most powerful<br />

predictor of EF and definitive extent of infarct size<br />

at follow-up.<br />

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S26 L. Agati et al.<br />

Fig. 3. Patient with acute apical myocardial infarction treated<br />

with primary angioplasty within 3 hours from symptom onset.<br />

No late enhancement or residual <strong>contrast</strong> defect is detected<br />

<strong>by</strong> either (A) magnetic resonance imaging or (B) myocardial<br />

<strong>contrast</strong> echo.<br />

Fig. 4. Patient with acute apical myocardial infarction treated<br />

with primary angioplasty within 3 hours from symptom onset.<br />

Similar extent of late enhancement and residual <strong>contrast</strong><br />

defect is detected both <strong>by</strong> (A) magnetic resonance imaging and<br />

(B) myocardial <strong>contrast</strong> echo.<br />

Fig. 5. Linear regression analysis shows a closer correlation between <strong>contrast</strong> defect at day 1 (CD%-T1) and wall motion abnormalities<br />

at follow up (WMA%-T3) (left panel) than between the initial (WMRA-T1) and final (WMA%-T3) extent of wall motion abnormalities<br />

(right panel).<br />

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<strong>Tissue</strong> <strong>viability</strong> <strong>by</strong> <strong>contrast</strong> <strong>echocardiography</strong> S27<br />

Fig. 6. ROC curves analysis considering all clinical, echocardiographic and angiographic parameters together. Contrast defect (CD%)<br />

shows the best sensitivity/specificity ratio. Abbreviations: RWMSI, regional wall motion score index; RCSI, regional <strong>contrast</strong> score<br />

index; WMA%, wall motion abnormalities; CD%, <strong>contrast</strong> defect; EDV, end-diastolic volume; EF, ejection fraction.<br />

Assessment of left ventricular remodelling<br />

After acute myocardial infarction, aging and time<br />

to treat are the major determinants of subsequent<br />

LV dysfunction, thus of the initial extent of wall<br />

motion abnormalities (WMA) and end-diastolic LV<br />

volume (EDV). All these parameters play a major<br />

role in inducing LV remodelling 39–46 . However, the<br />

initial extent of regional wall motion abnormalities<br />

provides indirect measures of infarct size whereas<br />

myocardial <strong>contrast</strong> <strong>echocardiography</strong> <strong>by</strong> assessing<br />

the extent of microvascular perfusion defect<br />

represents a direct measure of true infarct size.<br />

For these reasons, patients with similar extent<br />

of WMA and EDV soon after reperfusion may have<br />

different LV remodelling. The missing link is the<br />

microvascular damage, which explains why for<br />

similar volumes, ejection fraction and extent of<br />

regional wall motion abnormalities, LV remodelling<br />

can be different. LV remodelling may occur from<br />

24–48 hours after reperfusion to pre-discharge<br />

(early LV remodelling) or from pre-discharge to<br />

6 months (late LV remodelling). Different parameters<br />

may predict early and late remodelling. According<br />

to the GISSI 3 echo sub-study 43 EDV and the<br />

extent of WMA are important for predicting early<br />

remodelling; however for late remodelling prediction,<br />

EDV is not always so specific. Late remodelling<br />

is associated with progressive deterioration of<br />

global ventricular function over time: patients<br />

with extensive WMA and not significantly enlarged<br />

ventricular volume before discharge are at higher<br />

risk for progressive dilation and LV dysfunction.<br />

Nicolau et al. 44 pointed out for the first time the<br />

importance of microvascular perfusion, showing<br />

that the presence of ST-segment resolution after<br />

MI precludes the occurrence of remodelling.<br />

Similar conclusions were drawn <strong>by</strong> Bolognese<br />

et al. 42,45 demonstrating the correlation between<br />

microvascular dysfunction within the risk area and<br />

LV remodelling and survival at follow-up.<br />

Our data obtained during a multicentre Acute<br />

Myocardial Infarction Imaging (A.M.I.C.I) study<br />

conducted at 4 institutions in Italy on 120 patients<br />

with first acute ST-elevation acute myocardial<br />

infarction undergoing different reperfusion strategies<br />

within 6 hours from symptom onset 14,37,39,46 ,<br />

further confirm the key role of MCE in predicting<br />

LV remodelling. From multivariate analysis<br />

using Cox regression, the most important echo<br />

parameters for predicting LV remodelling at day 1<br />

after reperfusion are <strong>contrast</strong> defect (CD) and<br />

WMA extent and ejection fraction. However from<br />

analysis of ROC curves the most powerful predictor<br />

of LV remodelling with the best sensitivity/<br />

specificity ratio is the CD extent (Fig. 6).<br />

Considering all clinical, echocardiographic and<br />

angiographic parameters together (i.e. ST-segment<br />

reduction, all echo and angio parameters) the<br />

CD extent, TIMI post and ejection fraction are the<br />

most important parameters to predict remodelling<br />

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S28 L. Agati et al.<br />

Table 1<br />

Multivariate analysis: Cox regression<br />

Independent LVR predictors<br />

CD1 cut-off 21.7 (HR = 3.75; 95% CI: 1.19–11.80)<br />

TIMI post cut-off 3 (HR = 0.40; 95% CI: 0.17–0.99)<br />

Selecting only TIMI 3 after reperfusion<br />

CD1 cut-off 21.7 (HR = 4.91; 95% CI: 1.32–18.17)<br />

(Table 1). Therefore, <strong>contrast</strong> defect as compared<br />

to ST-segment reduction after reperfusion more<br />

strongly reflects the efficacy of reperfusion and<br />

it should be used routinely for assessing different<br />

reperfusion strategies. In the subset of patients<br />

reaching TIMI 3 score after reperfusion, multivariate<br />

analysis shows CD extent is the only independent<br />

parameter for LV remodelling (Table 1).<br />

Conclusions<br />

Microvascular damage is the missing link between<br />

LV remodelling infarct size and LV volumes.<br />

After acute myocardial infarction, MCE or MRI<br />

are the ideal methods for (1) assessing residual<br />

tissue <strong>viability</strong>, (2) following perfusional changes,<br />

and (3) evaluating the efficacy of treatment.<br />

The extent of scar tissue as detected <strong>by</strong> MRI<br />

or MCE can be considered as a new marker for<br />

identifying patients at high risk for sudden cardiac<br />

death caused <strong>by</strong> ventricular dysrhytmia, and it<br />

may be used for a better selection of patients as<br />

candidates for ICD implantation.<br />

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